This is an application for renewal of a project focussed on novel mechanisms involved in the regulation of hepatic glucose fluxes. During the next five years it will continue investigating mechanisms linking the availability of nutrients to the regulation of hepatic glucose fluxes. Specifically, it aims to examine the 'novel' hypothesis that insulin exerts some of its effects on the liver indirectly via modulation of hypothalamic neuronal pathways. The main working hypothesis is that activation of central pathways in response to increased availability of nutrients results in alterations in hepatic metabolism which are designed to couple energy signals with glucose output. Insulin regulation of hepatic glucose fluxes involves short-term and long-term mechanisms. The short-term mechanisms include direct effects on hepatic glycogenolysis and indirect effects such as inhibition of lipolysis. The long-term effects include modulation of gene transcription of key hepatic enzymes and perhaps changes in body composition and fat distribution. It is proposed herein to generate acute and prolonged bi-directional changes in hypothalamic insulin signaling using pharmacological and molecular approaches and determine their impact on hepatic glucose fluxes. It is also hypothesized that hypothalamic insulin signaling is prone to faltering in a susceptible animal models in the presence of prolonged over-feeding. Thus, the hypothesis that 'activating' hypothalamic insulin signaling will 'rescue' the severe hepatic insulin resistance in this model will be tested.